Human telomerase reverse transcriptase (TERT) is a constitutive self-tumor antigen and a potential target for cancer immunotherapy. In the past immunotherapy trials targeting TERT have failed to deliver on the promise of TERT as an immunotherapy target. For example, of 25 clinical studies performed using TERT as an antigen to induce an anti-tumor immune response, an objective clinical response has been shown in only 2 studies, and even then, with an overall response rate of less than 20%.
Telomerase reverse transcriptase (TERT) is a component of telomerase, the unique cellular enzyme that synthesizes the tandem 5′-TTAGGG-3′ exonucleotide repeats of telomeric DNA by reverse transcription of its own RNA template (TERC). The discovery of telomerase and telomerase-mediated extension of telomeric DNA solved both the end-replication problem, i.e., the mechanism by which telomeric DNA is maintained, and the end-protection problem. Human TERT is a self-antigen that consists of ˜1130 amino acids. In humans, telomerase activity by the canonical telomeric repeat amplification protocol (TRAP) assay is detected in >85% of tumors of various histological type, but not in normal tissues.
Tolerance is one major determinant in the development of one's individual immune response, and a major obstacle to develop immunotherapy to self-antigens such as telomerase. During ontogeny, tolerance shapes the repertoire by eliminating high affinity T cell precursors and sparing low affinity T cell precursors. Tumor growth can also promote peripheral tolerance if antigen-presenting cells activate T cells in the absence of costimulatory molecules (signal 2). In addition, certain T cell specificities may be lost over time due to senescence and exhaustion, or by remodeling cancer cell immunogenicity by immune editing.
Cellular responses to antigen by B and T cells are largely dictated by the human leukocyte antigens (HLA) present on an individual's cell surface. Intracellular antigens (e.g., viral proteins, self-proteins) are processed intracellularly, generally by the proteasome, to yield 8-10 amino acid polypeptides. 8-10-mers are loaded onto MHC class I HLA subtype A, B and C molecules for presentation to cytotoxic CD 8+ T cells. These cytotoxic T cells can then recognize and destroy cells carrying organisms (e.g., viruses) that express the protein. There are thousands of different HLA alleles split between the A, B and, C locus. These alleles are grouped into different types with designations such as A2 or B44. Some types are more common than others, with the A2 type being the most prevalent.